Method for diagnosing and treating irritable bowel syndrome

Abstract

Provided herein is a method of diagnosing irritable bowel syndrome in a subject involving determining the amount of at least one of Ruminococcus gnavus , phenethylamine, tryptamine and tyramine in a fecal sample obtained from the subject. Also provided is a method of treating irritable bowel syndrome in a subject in need thereof involving the administration of a therapeutically effective amount of a trace amine-associated receptor 1 inhibitor.

What is claimed is: 
     
         1 . A method of treating irritable bowel syndrome (IBS) in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a trace amine-associated receptor 1 (TAAR1) inhibitor to the subject. 
     
     
         2 . The method of  claim 1 , wherein the IBS is a diarrhea-predominant subtype (IBS-D). 
     
     
         3 . The method of  claim 1 , wherein the TAAR1 inhibitor selectively binds TAAR1. 
     
     
         4 . The method of  claim 1 , wherein the TAAR1 inhibitor is a small molecule. 
     
     
         5 . The method of  claim 1 , wherein the TAAR1 inhibitor is a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         n is 0, 1, 2 or 3, 
         p is 0 or 1; 
         R 1  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted by halogen, cycloalkyl, C 1 -C 6  alkoxy, NO 2 , —(CH 2 ) p S(O) 2 R, phenyl, morpholin-4-yl, pyrrolidin-1-yl, pyrazol-1-yl, piperidin-1-yl, 4-methyl-piperidin-1-yl, 4-cyano-piperidin-1-yl, 4-trifluoromethyl-piperidin 1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperidin-1-yl, piperazin-1-yl substituted by C(O)O—C 1 -C 6  alkyl, 1,1-dioxoisothiazolidin-2-yl, azepan-1-yl, azetidin-1-yl, 5,6-dihydro-4H-pyran-2-yl-, tetrahydro-pyran-2-yl, NR′R″ or C(O)CF 3 ; 
         R 2  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, cyano, NO 2 , —(CH 2 ) p S(O) 2 R, —OS(O) 2 NR′R″, C 1 -C 6  alkyl-O—C(═CH 2 )—, —C(O)—C 1 -C 6 alkyl, tetrahydro-furan-2-yl, morpholin-4-yl, pyrazol-1-yl, or —OC(O)—C 1 -C 6  alkyl, or R 1  and R 2  together with the corresponding C-atoms form a ring comprising —CH═CH—CH═CH— or —S—(CH 2 ) 4 —; 
         R 3  is hydrogen, halogen, C 1 -C 6  alkyl or C 1 -C 6  alkoxy; 
         R 4  is hydrogen, C 1 -C 6  alkoxy or halogen; 
         R 5  and R 7  are each independently hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NO 2 , cyano, C 1 -C 6  alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, phenyl, O-phenyl, —(CH 2 ) p S(O) 2 R, NHC(O)—C 1 -C 6  alkyl, C(O)—C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl or 2,5-dimethyl-imidazol-1-yl-methyl; 
         R 6  is hydrogen, C 1 -C 6  alkoxy, cyano, nitro, C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, C(O)O—C 1 -C 6  alkyl, C(O)O—(CH 2 ) 2 —NR′R″, oxazol-5-yl or halogen; or R 5  and R″ form together with the corresponding C-atoms a ring comprising —CH═CH—CH═CH—; 
         R 8  is hydrogen or C 1 -C 6  alkyl, 
         X is —C(R 9 )═ or —N═; 
         R 9  is hydrogen, C 1 -C 6  alkoxy, NO 2  or halogen; 
         R is C 1 -C 6  alkyl, morpholin-4-yl, pyrrolidin-1-yl, phenyl optionally substituted by halogen, CH 2 CN, NR′R″, piperidin-1-yl, piperazin-1-yl, 3,5-dimethyl-piperidin-1-yl, azetidin-1-yl or azepane-1-yl; and 
         R′ and R″ are each independently hydrogen, C 1 -C 6  alkyl, (CH 2 ) n -4-methylpiperidin-1-yl, (CH 2 ) n —C(O)—C 1 -C 6 alkyl, (CH 2 ) n -phenyl optionally substituted by halogen or (CH 2 )—O—C 1 -C 6  alkyl. 
       
     
     
         6 . The method of  claim 1 , wherein the TAAR1 inhibitor is N-(3-ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide. 
     
     
         7 . The method of  claim 1 , wherein the subject is a human, a non-human primate, a rodent, a canine, a feline, a bovine, or an equine. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human. 
     
     
         9 . The method of  claim 1 , wherein a fecal sample obtained from the subject comprises a higher amount of one or more markers selected from the group consisting of  Ruminococcus gnavus , phenethylamine, tryptamine and tyramine than an average amount of the one or more markers in fecal samples obtained from healthy controls. 
     
     
         10 . The method of  claim 1  further comprising the step of: providing a fecal sample obtained from the subject; determining the amount of one or more markers selected from the group consisting of phenethylamine, tryptamine and tyramine in the fecal sample; and determining based on the amount of the one or more markers in the fecal sample that the subject has IBS prior to the step of administering the TAAR1 inhibitor to the subject. 
     
     
         11 . The method of  claim 10 , wherein the one or more markers is phenethylamine and tyramine. 
     
     
         12 . The method of  claim 1  further comprising the step of: providing a fecal sample obtained from the subject; determining the amount of  Ruminococcus gnavus  in the fecal sample; and determining based on the amount of  Ruminococcus gnavus  in the fecal sample that the subject has IBS prior to the step of administering the TAAR1 inhibitor to the subject. 
     
     
         13 . A method of treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject in need thereof, the method comprising: providing a fecal sample obtained from the subject; determining the amount of one or more markers selected from the group consisting of  Ruminococcus gnavus , phenethylamine, tryptamine and tyramine in the fecal sample; determining based on the amount of the one or more markers in the fecal sample that the subject has IBS; and administering a therapeutically effective amount of a trace amine-associated receptor 1 (TAAR1) inhibitor to the subject. 
     
     
         14 . The method of  claim 13 , wherein the TAAR1 inhibitor is a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         n is 0, 1, 2 or 3; 
         p is 0 or 1; 
         R 1  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted by halogen, cycloalkyl, C 1 -C 6  alkoxy, NO 2 , —(CH 2 ) p S(O) 2 R, phenyl, morpholin-4-yl, pyrrolidin-1-yl, pyrazol-1-yl, piperidin-1-yl, 4-methyl-piperidin-1-yl, 4-cyano-piperidin-1-yl, 4-trifluoromethyl-piperidin 1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperidin-1-yl, piperazin-1-yl substituted by C(O)O—C 1 -C 6  alkyl, 1,1-dioxoisothiazolidin-2-yl, azepan-1-yl, azetidin-1-yl, 5,6-dihydro-4H-pyran-2-yl-, tetrahydro-pyran-2-yl, NR′R″ or C(O)CF 3 ; 
         R 2  is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, cyano, NO 2 , —(CH 2 ) p S(O) 2 R, —OS(O) 2 NR′R″, C 1 -C 6  alkyl-O—C(═CH 2 )—, —C(O)—C 1 -C 6  alkyl, tetrahydro-furan-2-yl, morpholin-4-yl, pyrazol-1-yl, or —OC(O)—C 1 -C 6  alkyl; or R 1  and R 2  together with the corresponding C-atoms form a ring comprising —CH═CH—CH═CH— or —S—(CH 2 ) 4 —; 
         R 3  is hydrogen, halogen, C 1 -C 6  alkyl or C 1 -C 6 alkoxy; 
         R 1  is hydrogen, C 1 -C 6  alkoxy or halogen; 
         R 5  and R 7  are each independently hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NO 2 , cyano, C 1 -C 6  alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, phenyl, O-phenyl, —(CH 2 ) p S(O) 2 R, NHC(O)—C 1 -C 6  alkyl, C(O)—C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl or 2,5-dimethyl-imidazol-1-yl-methyl; 
         R 6  is hydrogen, C 1 -C 6  alkoxy, cyano, nitro, C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkyl substituted by halogen, C 1 -C 6  alkoxy substituted by halogen, C(O)O—C 1 -C 6  alkyl, C(O)O—(CH 2 ) 2 —NR′R″, oxazol-5-yl or halogen; or R 5  and R 6  form together with the corresponding C-atoms a ring comprising —CH═CH—CH═CH—; 
         R 8  is hydrogen or C 1 -C 6  alkyl; 
         X is —C(R 9 )═ or —N═; 
         R 9  is hydrogen, C 1 -C 6  alkoxy, NO 2  or halogen; 
         R is C 1 -C 6  alkyl, morpholin-4-yl, pyrrolidin-1-yl, phenyl optionally substituted by halogen, CH 2 CN, NR′R″, piperidin-1-yl, piperazin-1-yl, 3,5-dimethyl-piperidin-1-yl, azetidin-1-yl or azepane-1-yl; and 
         R′ and R″ are each independently hydrogen, C 1 -C 6  alkyl, (CH 2 ) n -4-methylpiperidin-1-yl, (CH 2 ) n —C(O)—C 1 -C 6  alkyl, (CH 2 ) n -phenyl optionally substituted by halogen or (CH 2 ) n —O—C 1 -C 6  alkyl. 
       
     
     
         15 . The method of  claim 13 , wherein the TAAR1 inhibitor is N-(3-ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide. 
     
     
         16 . A method for diagnosing irritable bowel syndrome (IBS) in a subject, the method comprising: providing a fecal sample obtained from the subject; determining the amount of one or more markers selected from the group consisting of  Ruminococcus gnavus , phenethylamine, tryptamine and tyramine in the fecal sample; and determining based on the amount of the one or more markers in the fecal sample if the subject has IBS. 
     
     
         17 . The method of  claim 16 , wherein the IBS is a diarrhea-predominant subtype (IBS-D). 
     
     
         18 . The method of  claim 16 , wherein the one or more markers is phenethylamine and tyramine. 
     
     
         19 . The method of  claim 16  further comprising the step of administering a therapeutically effective amount of a trace amine-associated receptor 1 (TAAR1) inhibitor to the subject. 
     
     
         20 . The method of  claim 19 , wherein the TAAR1 inhibitor is N-(3-ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide.